Cumulin, an oocyte-secreted heterodimer of the transforming growth factor-beta family, is a potent activator of granulosa cells and improves oocyte quality

David G Mottershead, Satoshi Sugimura, Sara Al-Musawi, Jing-Jie Li, Dulama Richani, Melissa A White, Georgia A Martin, Andrew Trotta, Lesley J Ritter, Junyan Shi, Thomas D Mueller, Craig Anthony Harrison, Robert Gilchrist

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Abstract

Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-specific growth factors with central roles in mammalian reproduction, regulating species-specific fecundity, ovarian follicular somatic cell differentiation and oocyte quality. In the human, GDF9 is produced in a latent form, the mechanism of activation being an open question. Here, we produced a range of recombinant GDF9 and BMP15 variants, examined their in silico and physical interactions, and their effects on ovarian granulosa cells (GC) and oocytes. We found that the potent synergistic actions of GDF9 and BMP15 on GC can be attributed to the formation of a heterodimer, which we have termed cumulin. Structural modelling of cumulin revealed a dimerization interface identical to homodimeric GDF9 and BMP15, indicating likely formation of a stable complex. This was confirmed by generation of recombinant heterodimeric complexes of pro/mature domains (pro-cumulin) and covalent mature domains (cumulin). Both pro-cumulin and cumulin exhibited highly potent bioactivity on GC, activating both SMAD2/3 and SMAD1/5/8 signaling pathways, and promoting proliferation and expression of a set of genes associated with oocyte-regulated GC differentiation. Cumulin was more potent than pro-cumulin, pro-GDF9, pro-BMP15 or the two combined on GC. However, on cumulus-oocyte complexes, pro-cumulin was more effective than all other growth factors at notably improving oocyte quality as assessed by subsequent day 7 embryo development. Our results support a model of activation for human GDF9 dependant on cumulin formation through heterodimerization with BMP15. Oocyte-secreted cumulin is likely to be a central regulator of fertility in mono-ovular mammals.
Original languageEnglish
Pages (from-to)24007 - 24020
Number of pages14
JournalThe Journal of Biological Chemistry
Volume290
Issue number39
DOIs
Publication statusPublished - 2015

Cite this

Mottershead, D. G., Sugimura, S., Al-Musawi, S., Li, J-J., Richani, D., White, M. A., Martin, G. A., Trotta, A., Ritter, L. J., Shi, J., Mueller, T. D., Harrison, C. A., & Gilchrist, R. (2015). Cumulin, an oocyte-secreted heterodimer of the transforming growth factor-beta family, is a potent activator of granulosa cells and improves oocyte quality. The Journal of Biological Chemistry, 290(39), 24007 - 24020. https://doi.org/10.1074/jbc.M115.671487